The major goal of this research project is to determine the fundamental mechanisms of autoimmune disease and malignant lymphomas that develop spontaneously in autoimmune NZB mice and their crosses with the normal SWR mice. The NZB x SWR crosses have not only proved useful to dissect the role of various abnormalities of the NZB strain in the etiology of autoimmune disease, but are also helping us to identify the factors contributed by a normal strain in the development of lupus nephritis. AImost 100% of (NZB x SWR) F1 mice rapidly develop a lethally severe glomerulonephritis, in marked contrast to their autoimmune NZB parents. Monoclonal anti-DNA autoantibodies derived from the F1 mice by hybridoma technology will be analyzed for their antigen-binding specificity patterns, spectrotypes and allotypes. The F1-derived autoantibodies that are encoded by genes inherited from the NZB parent and those that are encoded by antibody genes from the SWR parent will be identified. Anti-idiotypic antibodies specific for these autoantibodies will be raised. These reagents will be used to study the inheritance and regulation of expression of these autoantibody idiotypes and their relation to nephritis development in NZB x SWR crosses. These autoantibody idiotypes will be deliberately suppressed to prevent the development of nephritis. The major genes determining the development of autoimmune disease will be identified and mapped by constucting recombinant inbred and congenic lines of mice. Finally, to define the mechanism of lymphoid malignancy, the cellular origin of the NZB lymphomas will be determined. The genomic structure of viruses produced by the lymphomas will be analyzed by T1 oligonucleotide fingerprinting and restriction endonuclease mapping techniques. Rearrangement of retroviral genes and cellular oncogenes in the lymphomas will also be studied. (MI)